STABILIZATION OF PROSTAGLANDIN COMPOSITIONS

Description

[0001] The present invention relates generally to prostaglandin compositions. In particular, the present invention relates to storage stable, pharmaceutical compositions containing prostaglandins and surfactants. As used herein, the term "prostaglandin" or "PG" shall refer to prostaglandins and derivatives and analogues thereof including pharmaceutically acceptable salts and esters, except as otherwise indicated by context.

[0002] Prostaglandins have notoriously low water solubility, and are generally unstable. Attempts have been made to solubilize and stabilize various prostaglandins by complexing them with different cyclodextrins. See, for example: EP 330 511 A2 (Ueno et al.) and EP 435 682 A2 (Wheeler). These attempts have met with varying success.

[0003] Surfactants and/or solubilizers have been used with other types of drugs having low water solubility. However, the addition of surfactants and/or solubilizers may enhance or adversely affect the chemical stability of drug compounds. See Surfactant Systems, Their Chemistry, Pharmacy, and Biology, (eds. Attwood et al.), Chapman and Hall, New York, 1983, Ch. 11, particularly pp. 698 - 714.

[0004] The use of non-ionic surfactants, such as polyethoxylated castor oils, as solubilizing agents is known. See, for example, US 4,960,799 (Nagy).

[0005] The use of non-ionic surfactants such as polyethoxylated castor oils in stable emulsions is also known. US 4,075,333 (Josse) discloses stable, intravenous emulsion formulations of vitamins. El-Sayed et al., Int. J. Pharm., 13:303-12 (1983) discloses stable oil-in-water emulsions of an antineoplastic drug. US 5,185,372 (Ushio et al.) discloses topically administrable ophthalmic formulations of vitamin A which are stable preparations in which a non-ionic surfactant is used to form an emulsion of vitamin A in an aqueous medium.

[0006] What is needed is a commercially viable, storage-stable prostaglandin composition.

SUMMARY OF THE INVENTION

[0007] The present invention is directed to the use of polyethoxylated castor oils in pharmaceutical compositions containing prostaglandins. It has now been unexpectedly discovered that the use of such polyethoxylated castor oils in such compositions enhances the chemical stability of prostaglandins in pharmaceutical compositions. The compositions of the present invention can be administered to the body in a variety of ways. When topically applied to the eye, the compositions of the present invention provide both initial and continual comfort.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008] 

Fig. 1 shows the stabilizing effect at different concentrations of a polyethoxylated castor oil in a preserved prostaglandin formulation at pH 5.0.

Fig. 2 compares the stabilizing effect of different surfactants in a preserved prostaglandin formulation at pH 5.0.

Fig. 3 compares the stabilizing effect of different surfactants in a preserved prostaglandin formulation at pH 7.4.

DETAILED DESCRIPTION OF THE INVENTION

[0009] Prostaglandin esters are difficult to formulate in storage-stable solutions as they tend to be hydrolytically unstable. In some instances, the parent acids of some prostaglandin esters are also unstable. The pharmaceutical compositions obtainable by the method of the present invention, however, are storage stable. These compositions contain a prostaglandin and a stability-enhancing amount of a polyethoxylated castor oil.

[0010] The polyethoxylated castor oils useful in the method of the present invention are commercially available, and include those classified as PEG-2 to PEG-200 castor oils, as well as those classified as PEG-5 to PEG-200 hydrogenated castor oils. Such polyethoxylated castor oils include those manufactured by Rhone-Poulenc (Cranbury, New Jersey) under the Alkamuls® brand, and those manufactured by BASF (Parsippany, New Jersey) under the Cremophor® brand. It is preferred to use the polyethoxylated castor oils classified as PEG-15 to PEG-50 castor oils, and more preferred to use PEG-30 to PEG-35 castor oils. It is most preferred to use those polyethoxylated castor oils known as Cremophor® EL and Alkamuls® EL-620.

[0011] The terms "prostaglandin" and "PG" are generally used to describe a class of compounds which are analogues and derivatives of prostanoic acid (1):

[0012] PG's may be further classified, for example, according to their 5-membered ring structure, using a letter designation:

Prostaglandins of the A series (PGA's):

Prostaglandins of the B series (PGB's):

Prostaglandins of the C series (PGC's):

Prostaglandins of the D series (PGD's):

Prostaglandins of the E series (PGE's):

Prostaglandins of the F series (PGF's):

Prostaglandins of the J series (PGJ's):

[0013] PG's may be further classified based on the number of unsaturated bonds on the side chain:

PG₁'s (13,14-unsaturated):

PG₂'s (13,14- and 5,6- unsaturated):

PG₃'s (13,14- 5,6- and 17,18- unsaturated):

[0014] The prostaglandins which may be utilized in the present invention include all pharmaceutically acceptable prostaglandins, their derivatives and analogues, and their pharmaceutically acceptable esters and salts. Such prostaglandins include the natural compounds: PGE₁, PGE₂, PGE₃, PGF₁₀₀, PGF₂₀₀, PGF₃₀₀ , PGD₂ and PGI₂ (prostacyclin), as well as analogues and derivatives of these compounds which have similar biological activities of either greater or lesser potencies. Analogues of the natural prostaglandins include: alkyl substitutions (e.g., 15-methyl or 16,16-dimethyl), which confer enhanced or sustained potency by reducing biological metabolism or alter selectivity of action; saturation (e.g., 13,14-dihydro) or unsaturation (e.g., 2,3-didehydro, 13,14-didehydro), which confer sustained potency by reducing biological metabolism or alter selectivity of action; deletions or replacements (e.g., 11-deoxy, 9-deoxo-9-methylene), chloro (or halogen) for oxygen (e.g., 9β-chloro), oxygen for carbon (e.g., 3-oxa), lower alkyl for oxygen (e.g., 9-methyl), hydrogen for oxygen (e.g., 1-CH₂OH,1-CH₂OAcyl) which enhance chemical stability and/or selectivity of action; and ω-chain modifications (e.g., 18,19,20-trinor-17-phenyl, 17,18,19,20-tetranor-16-phenoxy), which enhance selectivity of action and reduce biological metabolism. Derivatives of these prostaglandins include all pharmaceutically acceptable salts and esters, which may be attached to the 1-carboxyl group or any of the hydroxyl groups of the prostaglandin by use of the corresponding alcohol or organic acid reagent, as appropriate. It should be understood that the terms "analogues" and "derivatives" include compounds which exhibit functional and physical responses similar to those of prostaglandins per se.

[0015] Specific examples of prostaglandins which are useful in the present invention include the following compounds:

Compound No.

[0016] 

1. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid;

2. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

3. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester;

4. (5Z)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

5. (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

6. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid amide;

7. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid N,N-dimethylamide;

8. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclohexyl ester;

9. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclopentyl ester;

10. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid cyclopentyl ester;

11. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,2-dimethylpropyl ester,

12. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid adamantyl ester;

13. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,6-diisopropylphenyl ester;

14. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,6-dimethylphenyl ester;

15. (5Z, 13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid isopropyl ester;

16. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester;

17. (5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

18. (5E)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

19. (5Z)-(9R,11R)-9-chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prostenoic acid tertbutyl ester;

20. (5Z)-(9S,11R,15R)-3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostenoic acid isopropyl ester;

21. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-1-(dimethylamino)-3-oxa-16,17,18,19,20-pentanor-5-prostene-11,15-diol;

22. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenol;

23. (9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostynoic acid;

24. Latanoprost (PhXA41);

25. Cloprostenol isopropyl ester;

26. (5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5-prostenoic acid;

27. (5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloay)methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5,13-prostadienoic acid;

28. (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

29. (5Z)-(9S,11R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester;

30. (5Z, 13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid amide;

31. PGF_2α isopropyl ester; and

32. Fluprostenol isopropyl ester.

[0017] All of the foregoing compounds are known. Preferred prostaglandins for use in the compositions of the present invention are Compounds 2-8 above. Most preferred are Compounds 2 and 3 above. The structures of Compounds 2 and 3 are shown below.

[0018] The prostaglandin compositions obtainable by the method of the present invention contain one or more polyethoxylated castor oils in an amount effective to enhance the stability of the prostaglandin. As Figure 1 illustrates the stabilizing effect of the polyethoxylated castor oil increases with increasing polyethoxylated castor oil concentration. However, other factors may limit the amount of polyethoxylated castor oil to be utilized in the compositions of the present invention. For example, too much polyethoxylated castor oil should not be used in order to avoid adversely affecting the prostaglandin's pharmacologic activity.

[0019] In general, compositions of the present invention will include one or more polyethoxylated castor oils in an amount between 0.02 and 20.0 percent by weight (wt%) and one or more prostaglandins in an amount between 0.00001 and 0.2 wt%. It is preferred to use one or more polyethoxylated castor oils in an amount between 0.1 and 5.0 wt%, and it is especially preferred to use an amount between 0.5 and 2.0 wt%. It is preferred to use one or more prostaglandins in an amount between 0.0001 and 0.1 wt%, depending on the potency of the prostaglandin.

[0020] The compositions of the present invention may be administered to the body in a variety of ways. The compositions may be administered by mouth, by intravenous injection or by topical application to the skin, nose or eyes. Most preferred are compositions prepared for topical administration to the eye.

[0021] In addition to the above-described principal active ingredients, the compositions of the present invention may further comprise various formulatory ingredients, such as antimicrobial preservatives, tonicity agents, and buffers. Examples of suitable antimicrobial preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, Polyquad^• and other agents equally well known to those skilled in the art. Such preservatives, if utilized, will typically be employed in an amount between 0.001 and 1.0 wt%. Examples of suitable agents which may be utilized to adjust the tonicity or osmolality of the formulations include sodium chloride, potassium chloride, mannitol, dextrose, glycerine and propylene glycol. Such agents, if utilized, will be employed in an amount between 0.1 and 10.0 wt%. Examples of suitable buffering agents include acetic acid, citric acid, carbonic acid, phosphoric acid, boric acid, the pharmaceutically acceptable salts of the foregoing, and tromethamine. Such buffers, if utilized, will be employed in an amount between 0.001 and 1.0 wt%.

[0022] The compositions may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight, anionic mucomimetic polymers and gelling polysaccharides, such as those described in US 4,861,760 (Mazuel et al), US 4,911,920 (Jani et al.), and in commonly assigned US Serial No. 08/108,824 (Lang et al.).

[0023] As will be appreciated by those skilled in the art, the compositions may be formulated in various dosage forms suitable for topical ophthalmic delivery, including solutions, suspensions, emulsions, gels and erodible solid ocular inserts. The compositions are preferably aqueous, have a pH between 3.5 to 8.0 and an osmolality between 260 to 320 milliOsmoles per kilogram (mOsm/kg).

EXAMPLE

[0024] The following topically administrable ophthalmic formulations are representative of the compositions of the present invention.

	FORMULATION (wt%)
INGREDIENT	A	B	C
Compound 2	0.01	-	0.01
Compound 3	-	0.01	-
Cremophor• EL	0.5	0.5	0.5
Sodium Acetate (Trihydrate)	0.07	0.07	-
Tromethamine	-	-	0.12
Boric Acid	-	-	0.3
Mannitol	4.6	4.6	4.6
Disodium EDTA	0.1	0.1	0.1
Benzalkonium Chloride	0.01	0.01	0.01
NaOH and/or HCl	q.s. to pH 5	q.s. to pH 5	q.s. to pH 7
Purified Water	q.s. to 100%	q.s. to 100%	q.s. to 100%

Preparation of Formulations A-C:

[0025] To a clean glass vessel of appropriate size was added approximately 75% of the batch volume of water. To this was sequentially added sodium acetate, tromethamine, boric acid, mannitol, EDTA, benzalkonium chloride and Cremophor^• EL so that there was complete dissolution of one ingredient prior to the addition of the next ingredient. Next the pH of the solution was adjusted using NaOH and/or HCl, and the water was added to bring the volume to 100%.

[0026] In a separate clean glass vessel, the appropriate quantity of prostaglandin was added, followed by the appropriate quantity of the vehicle whose preparation was described above. The vessel was then tightly capped and sonicated in an ultrasonic bath for one hour or alternatively stirred with a magnetic stir bar overnight, until the prostaglandin was completely dissolved. The resulting solution was then sterile filtered (0.2 micron filter) into sterile containers. These containers were then aseptically plugged, capped and labelled.

[0027] The stabilizing effect of polyethoxylated castor oils in the compositions of the present invention was evaluated according to the following procedure.

1. Pipet the required quantity of 1% w/v prostaglandin ethanolic stock solution into 1.5 mL high performance liquid chromatograph (HPLC) sample vials.

2. Dry the sample vials under a stream of helium.

3. Add 1 mL of the appropriate vehicle (or HPLC mobile phase for standards).

4. Sonicate the vials one hour to dissolve the prostaglandin.

5. Run initial HPLC assays.

6. Place the HPLC sample vials into 20cc scintillation vials with several mLs of deionized water and cap tightly. (Note: This prevents loss due to evaporation.) Standards are stored with HPLC mobile phase in the scintillation vial.

7. Place the vials in the appropriate controlled temperature ovens and reassay periodically by HPLC. Standards are stored in a refrigerator.

8. HPLC Data Analysis: Divide Sample Peak Area by Standard Peak Area and multiply by 100 to obtain Percent of Standard for each sample at each time point.

9. Plot Percent of Standard versus time on a semilogarithmic graph. Fit a monoexponential equation to the data. The slope times 2.303 is the apparent first-order degradation rate constant for each plot (Note: The factor of 2.303 converts common logarithm to natural logarithm).

[0028] Figure 1 demonstrates the effect of increasing polyethoxylated castor oil concentration in Formulation A. The chemical stability of a given concentration of prostaglandin is increased as the concentration of Cremophor® EL is increased.

[0029] Figure 2 demonstrates the superior stabilizing effect of the polyethoxylated castor oils, Cremophor® EL and Alkamuls® EL-620, over Polysorbate 80 in a type A Formulation (pH = 5.0).

[0030] Figure 3 demonstrates the superior stabilizing effect of the polyethoxylated castor oils, Cremophor® EL and Alkamuls® EL-620, over Polysorbate 80 in a type C formulation (pH = 7.4).

[0031] The data shown in Figures 1-3 were generated using a Phenomenex 250 X 4.6 mm HPLC column with Spherisorb^• 10 ODS(2) packing. The mobile phase was 50/50 acetonitrile/0.1 % phosphoric acid at pH 3 with NaOH, 5mM tetrabutylammonium hydroxide, and 5 mM sodium dodecylsulfate. The flow rate was 2 mL/minute, the detection was 190 - 192 nm UV, and the injection quantity was 25 mcL.

Claims

1. A method of enhancing the chemical stability of pharmaceutical prostaglandin composition comprising adding a polyethoxylated castor oil to the composition.

2. The method of Claim 1 wherein the polyethoxylated castor oil is present at a concentration between 0.02 wt% and 20.0 wt%.

3. The method of Claim 2 wherein the polyethoxylated castor oil is present at a concentration between 0.1 wt% and 5.0 wt%.

4. The method of Claim 3 wherein the polyethoxylated castor oil is present at a concentration between 0.5 wt% and 2.0 wt%.

5. The method of Claim 1 wherein the polyethoxylated castor oil is selected from the group consisting of: PEG-2 to PEG-200 castor oils and PEG-5 to PEG-200 hydrogenated castor oils.

6. The method of Claim 5 wherein the polyethoxylated castor oil is selected from the group consisting of: PEG-15 to PEG-50 castor oils.

7. The method of Claim 6 wherein the polyethoxylated castor oil is selected from the group consisting of: PEG-30 to PEG-35 castor oils.

8. The method of Claim 1 wherein the prostaglandin is selected from the group consisting of: (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester; (5Z)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid amide; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid N,N-dimethylamide; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclohexyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclopentyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid cyclopentyl cster; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,2-dimethylpropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid adamantyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,6-diisopropylphenyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 2,6-dimethylphenyl ester; (5Z, 13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester; (5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; (5E)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R)-9-chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prostenoic acid tertbutyl ester; (5Z)-(9S,11R,15R)-3-oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-1-(dimethylaminc)-3-oxa-16,17,18,19,20-pentanor-5-prostene-11,15-diol; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenol; 9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostynoic acid; latanoprost (PhXA41); cloprostenol isopropyl ester, (5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5-prostenoic acid; (5Z)-(9S,11R,15R)-1-decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorophenyl)oxy]-17,18,19,20-tetranor-5,13-prostadienoic acid; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9S,11R,15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; (5Z, 13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophenoxy)-17,18,19,20-tetranor-5,13-prostadienoic acid amide; PGF_2α isopropyl ester; and fluprostenol isopropyl ester.

9. The method of Claim 8 wherein the prostaglandin is selected from the group consisting of: (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester; (5Z)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid amide; (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid N,N-dimethylamide; and (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid 1-methylcyclohexyl ester.

10. The method of Claim 9 wherein the prostaglandin is selected from the group consisting of (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid isopropyl ester and (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenoic acid t-butyl ester.

11. The method of Claim 1 wherein the prostaglandin is present at a concentration between 0.0001 wt% and 0.1 wt%.

12. The method of Claim 1 wherein the composition is a topically administrable ophthalmic composition.

Ansprüche

1. Verfahren zur Verbesserung der chemischen Stabilität einer pharmazeutischen Prostaglandinzusammensetzung umfassend, dass ein polyethoxyliertes Rizinusöl der Zusammensetzung zugegeben wird.

2. Verfahren nach Anspruch 1, wobei das polyethoxylierte Rizinusöl in einer Konzentration von 0,02 bis 20,0 Gew.-% vorhanden ist.

3. Verfahren nach Anspruch 2, wobei das polyethoxylierte Rizinusöl in einer Konzentration von 0,1 bis 5,0 Gew.-% vorhanden ist.

4. Verfahren nach Anspruch 3, wobei das polyethoxylierte Rizinusöl in einer Konzentration von 0,5 bis 2,0 Gew.-% vorhanden ist.

5. Verfahren nach Anspruch 1, wobei das polyethoxylierte Rizinusöl ausgewählt ist aus der Gruppe bestehend aus: PEG-2- bis PEG-200-Rizinusölen und hydrierten PEG-5- bis PEG-200- Rizinusölen.

6. Verfahren nach Anspruch 5, wobei das polyethoxylierte Rizinusöl ausgewählt ist aus der Gruppe bestehend aus PEG-15- bis PEG-50-Rizinusölen.

7. Verfahren nach Anspruch 6, wobei das polyethoxylierte Rizinusöl ausgewählt ist aus der Gruppe bestehend aus PEG-30- bis PEG-35-Rizinusölen.

8. Verfahren nach Anspruch 1, wobei das Prostaglandin ausgewählt ist aus der Gruppe bestehend aus:

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-isopropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-t-butyl-ester;

(5Z)-(9S,11R,15R)-15-Cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäure-isopropylester;

(5Z)-(9R,11R,15S)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-isopropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureamid;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-N,N-dimethylamid;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-1-methyl-cyclohexylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-1-methyl-cyclopentylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäurecyclopentyl-ester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-2,2-dimethylpropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-adamantyl-ester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-2,6-diisopropylphenylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-2,6-dimethylphenylester;

(5Z,13E)-(9S,11R,15R)-3-Oxa-9,11,15-trihydroxy-16-(3-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadiensäure-isopropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11-hydroxy-15-methoxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-t-butylester;

(5Z)-(9R,11R,15R)-15-Cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäure-isopropylester;

(5E)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-isopropyl-ester;

(5Z)-(9R,11R)-9-Chlor-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prostensäure-tert.-butyl-ester;

(5Z)-(9S,11R,15R)-3-Oxa-17-phenyl-9,11,15-trihydroxy-18,19,20-trinor-5-prostensäure-isopropylester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-1-(dimethyl-amino)-3-oxa-16,17,18,19,20-pentanor-5-prosten-11,15-diol;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostenol; (9R,11R,15R)-9-Chlor-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostinsäure;

Latanoprost (PhXA41); Cloprostenol-isopropylester; (5Z)-(9S,11R,15R)-1-Decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorphenyl)oxy]-17,18,19,20-tetranor-5-prostensäure;

(5Z)-(9S,11R,15R)-1-Decarboxy-1-(pivaloyloxy)methyl-9,11,15-trihydroxy-16-[(3-chlorphenyl)oxy]-17,18,19,20-tetranor-5,13-prostadiensäure;

(5Z)-(9R,11R,15R)-9-Chlor-15-Cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5-prostensäure-isopropylester;

(5Z) - (9S, 11R, 15S) -15-Cyclohexyl-9, 11, 15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäure-isopropylester;

(5Z,13E)-(9S,11R,15R)-9,11,15-Trihydroxy-16-(3-chlorphenoxy)-17,18,19,20-tetranor-5,13-prostadiensäure-amid; PGF_2α-Isopropylester und Fluprostenol-isopropylester.

9. Verfahren nach Anspruch 8, wobei das Prostaglandin ausgewählt ist aus der Gruppe bestehend aus:

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-isopropyl-ester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-t-butylester;

(5Z)-(9S,11R,15R)-15-Cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prostensäure-isopropylester;

(5Z)-(9R,11R,15S)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-isopropyl-ester;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäureamid;

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-N,N-dimethylamid und

(5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-1-methylcyclohexylester.

10. Verfahren nach Anspruch 9, wobei das Prostaglandin ausgewählt ist aus der Gruppe bestehend aus (5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-isopropyl-ester und (5Z)-(9R,11R,15R)-9-Chlor-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostensäure-t-butylester.

11. Verfahren nach Anspruch 1, wobei das Prostaglandin in einer Konzentration von 0,0001 bis 0,1 Gew.-% vorhanden ist.

12. Verfahren nach Anspruch 1, wobei die Zusammensetzung eine topisch verabreichbare ophthalmische Zusammensetzung ist.

Revendications

1. Procédé d'amélioration de la stabilité chimique d'une composition pharmaceutique de prostaglandine, comprenant l'addition d'huile de ricin polyéthoxylée à la composition.

2. Procédé selon la revendication 1, caractérisé en ce que l'huile de ricin polyéthoxylée est présente à raison de 0,02 à 20,0% en poids.

3. Procédé selon la revendication 2, caractérisé en ce que l'huile de ricin polyéthoxylée est présente à raison de 0,1 à 5,0% en poids.

4. Procédé selon la revendication 3, caractérisé en ce que l'huile de ricin polyéthoxylée est présente à raison de 0,5 à 2,0% en poids.

5. Procédé selon la revendication 1, caractérisé en ce que l'huile de ricin polyéthoxylée est choisie dans le groupe constitué par les huiles de ricin PEG-2 à PEG-200 et les huiles de ricin hydrogénées PEG-5 à PEG-200.

6. Procédé selon la revendication 5, caractérisé en ce que l'huile de ricin polyéthoxylée est choisie dans le groupe constitué par les huiles de ricin PEG-15 à PEG-50.

7. Procédé selon la revendication 6, caractérisé en ce que l'huile de ricin polyéthoxylée est choisie dans le groupe constitué par les huiles de ricin PEG-30 à PEG-35.

8. Procédé selon la revendication 1, caractérisé en ce que la prostaglandine est choisie dans le groupe formé par: l'acide (5Z)-(9R,11 R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, l'ester isopropylique de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dlydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, l'ester t-butylique de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclo-hexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, l'ester isopropylique de l'acide (5Z)-(9S,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydoxy-16,17,18,19,20-pentanor-5-prosténoïque, l'ester isopropylique de l'acide (5Z)-(9R,11R,15S)-9-chloro-15-cyclo-hexyl-11,15dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, l'amide de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque; le NN-diméthylamide de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclo-hexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, le 1-méthylcyclohexylester de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy.-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, le 1-méthylcyclopentylester de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, le cyclopentylester de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclo-hexyl-11,15-dihydroxy-3-oxa-16,17,18,19@O-pentanor-5-prosténoïque, le 2,2-diméthylpropylester de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihyctroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, l'adamantylester de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclo-hexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, le 2,6-diisopropyl-phénylester de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, le 2,6-diméthylphénylester de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prostadiénoïque, l'isopropylester de l'acide (5Z,13E)-(9S,11R,15R)-3-oxa-9,11,15-trihydroxy-16-(3-chlorophénoxy)-17,18,19,20-tétranor-5,13-prosténoïque, le t-butylester de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-1-hydroxy-15-méthoxy.3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, l'isopropylester de l'acide (5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prosténoïque, l'isopropylester de l'acide (5E)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, le tert.-butylester de l'acide (5Z)-(9R,IIR)-9-chloro-15-cyclohexyl-11-hydroxy-3-oxa-15-oxo-16,17,18,19,20-pentanor-5-prosténoïque, l'isopropylester de l'acide (5Z)-(9S,11R,15R)-3-oxa-17-phényl-9,11,15-trihydroxy-18,19,20-trinor-5- prosténoïque, le (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-1-(diméthylamino)-3-oxa-16,17,18,19,20-pentanor-5-prostène-11,15-diol, le (52)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténol, l'acide (9R,11R,15R)-9-chloro-15-cyclohexyl-11-hydroxy-3-thia-16,17,18,19,20-pentanor-13-prostynoïque, le Latanoprost (PhXA41), l'ester isopropylique de cloprosténol, l'acide (5Z)-(9S,11R,15R)-1-décarboxy-1-(pivaloyloxy)méthyl-9,11,15-trihydroxy-16-[(3-chlorophényl)-oxy]-17,18,19,20-tétranor-5-prosténoïque, l'acide (5Z)-(9S,11R,15,R)-1-décarboxy-1-(pivaloyloxy)-méthyl-9,11,15-trihydroxy-16-[(3-chlorophényl)-oxy]-17,18,19,20-tétranor-5,13-prostadiénoïque, l'isopropylester de l'acide(5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20- pentanor-5-prosténoïque, l'isopropylester de l'acide (5Z)-(9S,11R-15S)-15-cyclohexyl-9,11,15-trihydroxy-16,17,18,19,20-pentanor- 5-prosténoïque, l'amide de l'acide (5Z, 13E)-(9S,11R,15R)-9,11,15-trihydroxy-16-(3-chlorophénoxy)-17,18,19,20-tétranor-5,13-prostadiénoïque, l'ester isopropylique de PGF₂ α et l'ester isopropylique de fluprosténol.

9. Procédé selon la revendication 8, caractérisé en ce que la prostaglandine est choisie dans le groupe formé par l'ester isopropylique de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, le t-butylester de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5- prosténoïque, l'ester isopropylique de l'acide (5Z)-(9R,11R,15R)-15-cyclohexyl-3-oxa-9,11,15-trihydroxy-16,17,18,19,20-pentanor-5-prosténoïque, l'ester t-butylique de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclo-hexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, l'amide de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, le NN-diméthylamide de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclo-hexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque, et le v1-méthylcyclohexylester de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy.-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque.

10. Procédé selon la revendication 9, caractérisé en ce que la prostaglandine est choisie dans le groupe formé par l'ester isopropylique de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-11,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque et le t-butylester de l'acide (5Z)-(9R,11R,15R)-9-chloro-15-cyclohexyl-1 1,15-dihydroxy-3-oxa-16,17,18,19,20-pentanor-5-prosténoïque.

11. Procédé selon la revendication 1, caractérisé en ce que la prostaglandine est présente à une concentration de 0,0001 à 0,1% en poids.

12. Procédé selon la revendication 1, caractérisé en ce que la composition est une composition ophtalmique à application locale.

Drawing